Benzhydryl ethers of 10-(hydroxyethylpiperazinopropyl) phenothiazines



BENZHYDRYL ETHEIS OF IG-(HYDROXYETHYL- I PIPERAZINOPROPYL) PHENOTHIAZINES Harry LouisYale and Jack Bernstein, New Brunswick, 7 v

and Francis Alexander Sowinski, Nixon, N.J., assignors to Olin Mathieson Chemical Corporation, New York, N .Y., a corporation of Virginia 1 No Drawing. Filed Feb. 28, 1963,'Ser.' No. 261,880

6 Claims. (Cl. 260-443) This invention relates to new ethers of phenothiazines having valuable therapeutic properties and processes for the preparation thereof.

The new therapeutitcally active compounds of this invention include phenothiazines of the general formula:

' R (lJmoIncHVN N-(CHzCH O) -OH N X I l and non-toxic acid-addition salts thereof; wherein r is one or two; and X, R and R are the same or different and each represents hydrogen, halogen (preferably chloro), trifluoromethyl, lower alkyl, lower alkoxy, lower alkanoyl, lower 'alkylmercapto, trifluoromethylmercapto, trifluoromethoxy, lower alkylsulfonyl (preferably methylsulfonyl) and N,N-dimethylaminosulfonyl.

The preferred compounds are thosewherein r is one, R and R are hydrogen and X is chloro or trifiuoroinethyl.

As the salts of the bases of this invention, those coming within the purview of the invention include the acidaddition salts, particularly, the non-toxic acid, addition salts. Acidsuseful for preparing the acid-addition salts, include, interalia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid, and organic acids, such as oxalic, maleic, fumaric, tartaric, citric, acetic, succinic and pamoic acid.

The compounds of this invention are therapeutically active compounds which are utilizable both as tranquilizing (ataractic) agents, and thus may be used in the treatment of depressed psychotic states, and as antihistamines. For these purposes they may be administered orally or parenterally in conventional dosage forms such as tablets, capsules, injectables or the like by incorporatingthe appropriate dose of the compound with carriers according to accepted pharmaceutical practices. The compounds of this invention are superior to known phenothiazine tranquilizing agents inthat they possess an antagonism to the extrapyraniidal syndome, a side-effect frequently associatedwith therapy by these agents.

The compounds of this invention can be prepared by interacting a compound of the general Formula I:

3,169,952 Patented Feb 16, 1965 wherein X and r are as hereinbefore defined, with a diphenylmethyl halide (preferably chloride) of the formula:

phenothiazine reactants may be mentioned:

10- [3- Z-hydroxye-thyl) piperazinopropyl] phenothiazine;

10- 3- (Z-hydroxyethyl) piperazinopropyl] -2-halophenothiazines, such as 10- 3- (Z-hydroxyethyl) piperazinopropyl] -2- chlorophenothiazine;

10- 3- Z-hydroxyethyl (piperazinopropyfl a2 trifluoromethylphenothiazine;

10- 3- Z-hydroxyethoxyethyl) piperazinopropyl] -2- halo-phenothiazines, such as 10'- 3- (2-hydroxyethoxyethyl) piperazinopropyl] -2- chlorophenothiazine;

10-[ 3- (Z-hydroxyethoxyethyl piperazinopropyl] -2- trifluoromethylphenothiazine; r

1Q- 3- (2-hydroxyethyl) piperazinopropyl] -2- (lower alkyl) -phenothiazines, such as 10- 3- (l'2-hydroxyethyl pip erazinopropyl] 2- methylphenothiazine;

10- 3- Z-hydroxyethyl) pip erazinopropyl] -2- (lower alkoxy) phenothiazines, such as l 10- 3- Z-hydroxyethyl) piperazinopropyl] -2- methoxyphenothiazine;

l0- 3- (2-hydroxyethyl)piperazinopropyl] -2- (lower alkanoyl) phenothiazines, such as 10- [3-( Z-hydroxyethyl) piperazinopropyl] -2- propionylphenothiazine;

1O 3- Z-hydroxyethyl piperazinopropyl] 2- (lower alkyl mercapto phenothiazines, such as 10-[3-(Z-hydroxyethyl)piperazinopropyl] -2- methy]mercaptophenothiazine; a

10- [3- (Z-hydroxyethyl) piperazinopropyl] -2- trifiuoromethylmercaptophenothiazine;

10-[3- (Z-hydroxyethyl)piperazinopropyl]-2- trifluoromethoxyphenothiazine;

10- 3- (2-hydroxyethy1 )piperazinopropyl] -2- methylsulfonylphenothiazine and 10-[ 3- (Z-hydroxyethyl piperazinopropyl] -2-N,N-

dimethylaminosulfonylphenothiazine.

Among the suitable diphenylmethyl chloridereactants may be mentioned: 1

benzhydryl chloride;

a-(halophenyhbenzyl chlorides, such as u-(o-bromophenyDbenzyl chloride, a-(p-chlorophenyDbenzyl chloride and ot-(m-fluorophenyDbenzyl' chloride; a-[(trifluoromethyl)phenyl]benzyl chlorides, such as or (P-trifluoromethyl phenyl] benzyl chloride and ot-'[ (o-trifluoromethyl phenyl] benzyl chloride;

oc-(lOWCI alkyl-pheriyDbenzyl chlorides, such as a-.(p-tolyl)benzyl chloride, a-(p-ethylphenyDbenzyl chloride, and a-(m-isopropylphenyl) benzyl chloride; u-(lower alkoxyphenyl)benzyl chlorides, such as a-(p-methoxyphenyDbenzyl chloride; a-(lower alkyl mercaptophenyl benzyl chlorides, such as a-(p-methylmercaptophenyl)benzyl chloride and a-(o-ethylmercaptophenyl)benzyl chloride; u-[(2-trifiuoromethoxy)phenylJbenzyl chlorides, such as oc-l (p-trifluoromethoxy) phenyl] benzyl chloride; a-(N,N-dimethylaminosulfonylphenyl)benzyl chlorides,

such as cz- (p-N,N-dimethylaminosulfonylphenyl)benzyl chloride; oc-(lOWCl alkylsulfonylphenyl)benzyl chlorides, such as a- (p-methylsulfonylphenyl)benzyl chloride; a,a-di(halophenyl)methyl chlorides, such as a,a-di(p-chlorophenyl)methyl chloride and t1- (p-chlorophenyl) -oc- (p-bromophenyl) methyl chloride; a-halophenyl-a-(lower alkyl phenyl)methyl chlorides,

such as a- (p-chlorophenyl) -oc- (p-tolyl) methyl chloride; oc,oc-dl(lOW81' alkyl phenyl)methyl chlorides, such as a,a-di(p-tolyl)methyl chloride; and a-(lower alkoxyphenyl)-a-(halophenyl)methyl chlorides.

The substituted benzyl chlorides are prepared by known methods. Thus, as a typical procedure, p-trifluoromethoxybenzoic acid (prepared by the sequence: ethyl p-hydroXybenzoateethyl p-trichloromethoxybenzoateethyl p trifluoromethoxybenzoate p trifiuoromethoxybenzoic acidp trifiuoromethoxybenzoyl chloride p trifluoromethoxyphenyl phenyl ketone a(p-trifluoromethoxyphenyl)benzyl chloride.

Alternatively, the compounds of this invention can be prepared by interacting a compound of the general Formula II:

wherein X and r are as hereinbefore defined and Z is halogen, preferably chlorine or bromine, with diphenyl carbinol of the formula:

wherein R and R are as hereinbefore defined, in the presence of a condensing agent such as sodium hydride, in an organic solvent, such as toluene and tetrahydrofuran. The compounds of Formula II can be prepared as disclosed in application Serial No. 254,459, filed January 28, 1963, and application Serial No. 261,866, filed February 28, 1963, by interacting a compound of Formula I with a thionyl halide, such as thionyl chloride and thionyl bromide.

Among the suitable phenothiazine reactants of the Formula II may be mentioned:

- 3- 2-chloroethyl piperazinopropyl] phenothiazine;

10- 3- 2-bromoethyl piperazinopropyl] -2-halophenothiazines, such as 10- 3-( 2-bromoethyl) piperazinopropyl] -2-chlorophenothiazine;

10- 3- 2-bromoethyl piperazinopropyl] -2-trifluoromethyl) phenothiazine I 10- 3- (Z-chloroethoxyethyl piperazinopropyl] -2-halophenothiazines, such as 10- 3- (Z-chloroethoxyethyl piperazinopropyl] -2-chlorophenothiazine;

10-[3-(Z-chloroethoxyethyl)piperazinopropyl]-2-(trifluoromethyl) -pheno thiazine;

10-[3-(2-chloroethyl) piperazinopropyl] -2- (lower alkyl) phenothiazines, such as 10- 3- 2-chloroethyl) piperazinopropyl] -2-methylphenothiazine;

10- 3- (2-chloroethyl) piperazinopropyl] -2- (lower alkoxy)phenothiazines, such as 10-[3-(2-chloroethyl)piperazinopropyl]-2-methoxyphenothiazine;

l0-[3-(2-chloroethyl)piperazinopropyl]-2-(lower alkanoyl)phenothiazines, such as 10-[3-(2-chloroethyl)piperazinopropyl]-2-propionylphenothiazine;

10- 3-( 2-chloroethyl piperazinopropyl] -2- (lower alkyl mercapto)phenothiazines, such as 10- l 3- (2-chloroethyl piperazinopropyl] -2-methylmercaptophenothiazine;

10- 3- 2-chloroethyl piperazinopropyl] -2-trifiuoromethylmercaptophenothiazine;

10-[3-(2-chloroethyl)piperazinopropyl]-2-trifluoromethoxyphenothiazine;

10-[3-(2-chloroethyl)piperazinopropyl]-2-methylsulfonylphenothiazine and 10-[3-(Z-chloroethyl)piperazinopropyl1-2-N,N-dimethylaminosulfonylphenothiazine.

The compounds of this invention can also be prepared by interacting a compound of the general Formula III:

(III) wherein X is as hereinbefore defined with a compound of the general Formula IV:

Z(CH;,OHaO):CH

wherein Z, r, R and R are as hereinbefore defined, in an organic solvent, such as benzene, toluene, methyl ethyl ketone or tetrahydr'ofuran, in the presence of a basic compound, such as barium hydroxide. Compounds IV can be prepared by the interaction first of a benzhydrol with sodium hydride, reaction of the sodium salt formed with chloroethanol or chloroethyl hydroxyethyl ether to give a 2-benzhydryloxyethanol or 2-benzhydryloxyethyl hydroxyethyl ether and interaction of the last mentioned compounds with thionyl chloride.

The free bases of this invention can be converted to acid-addition salts by treatment with the desired acid. This reaction is preferably conducted in an inert organic solvent under substantially anhydrous conditions by treating the base with the acid, whereby the acid-addition salt is formed.

The following examples illustrate the invention (all temperatures being in centi'grade):

Example 1.-4-{3-[2-(trifluoromethyl)phenothiazin-I0- yl]propyl}-piperazinoethyl benzhydryl ether (a) Preparation of 4-{3-[2-(trifluoromethyl)phenothiazin-I O-yl] -pr0pyl}-piperazinaethyl Z-dimethylaminoethyl ether, hydrochloride salt.To 32.8 g. of 4-{3-[2-(trifluoromethyl)phenothiazin 10 yl] propyl}piperazinoethanol in 125 m1. of dry toluene is added slowly 3.55 g. of a 50% dispersion of sodium hydride in mineral oil. Following the vigorous reaction, the mixture is refluxed for an hour, cooled and treated with 15.0 g. of benzhydryl chloride. Subsequently, the mixture is heated at for 16 hours, cooled and filtered. The filtrate is washed with water and then with 10% aqueous hydrochloric acid.

The hydrochloric acid extracts obtained in step a are cooled, an excess of 40% aqueous potassium hydroxide is added and the liberated oil extracted into ether. The ether extnacts are concentrated to give 4-{3-[2-(trifluoron1ethyl)phenothiazin-lO-yl]propyl}piperazinoethyl benzhydryl ether as a pale yellow oil. I

Example 2 .4- [3-(Z-Chlorophenothiazin-Z O-yl) propyl] piperazinoethyl benzhydryl ether Following the procedure of Example 1 but substituting an equivalent amount of 4-[3(2-chlorophenothiazin-10- yl)propyl]piperazinoethariol, for the pipenazinoethanol used in the example, 4-[3-(Z-chlo-rophenothiazin-10-yl)- propyl]piperazinoethyl benzyhydryl ether is formed.

Example 3.4- [3-(phenothiazirt-J0-yl) propyl] piperazinoethyl benzhydryl ether yl phenothiazin- 10.-yl] propyl}-piperazinoethy1 a- (p-chlorophenyl)benzyl ether is obtained' Example 15.4-{3- [Z-(trifluOramethyZ) phenothiazin-JO- yl]pr0pyl}-piperazinoethyl. a-(p-tolyllbenzyl ether Following the procedure of Example 1 but substituting an equivalent amount of a-(p-tolyDbe'nzyl chloride for the benzhydryl chloride, 4-{3-[2-trifiuoromethyl) phenothiazin-l0-yl]propyl} piperazinoethyl (p tolyl)- benzyl ether is obtained.

Example ]6.-4-{3 [2-( trifluoromelhyl) phenothiazin-l 0- yl] propyl}-piperazin0ethyl ap-methoxyphenyl) benzyl ether Following the procedure of Example 1 but substituting an equivalent amount of oc(p-methoxyphenyl)benzyl chloride for the benzhydryl chloride, there is obtained perazinoethyl a(p-methoxyphenyl)- benzyl ether.

In a similar manner, by substituting the indicated chloride for the benzhydryl chloride in the procedure of Example 1, the indicated ether of 4-{3-[2-(trifluorometh-' yl)phenothiazin l0 yl]propyl} piperazinoethyl is obtained:

Example 1 and following the procedure of the example,

the indicated Z-substrtuted phenothiazine ether 15 formed:

Example Starting Material Product Formed: Example Swims Materlal Ether Formed Benzhydryl Ether ot 17 a-(p-Trifluoromethylphea-(p lrifiuoromethylphe- 4 4-[3-(2-Methylpheuothiazin- 4-[3-(2-Methylphenothiazinnyh zyl o e. nyl)benzyl.

10-y1)propyl]piperazinol0-yl)propyl]piperazino- 18 -(pethy m c p p e- -lpp p ethanol, ethyl, nyl)benzyl chlorlde. nyDbenzyl.

5 4-[3-(2Methoxyphenothia- 4-[3-(2-Methoxyphenothia- 9 -(pfi o h yp -(pyp zin-10-y1)propyl]piperzin-lO-yDpropyHpipery 3f YD YL azinoethanol, azinoethyL 20 a-(p-N,N-d1methylam1noa-(p-N,N-dimethylaminoe 4-[3-(Z-Propionylphenothia- 4-[3-(2-Propionylpheuothiau p yby y p y zin-l0-yl)pr0pyl]piperzin-l0-yl)propyl]piperri azinoethanol. azinoethyl. 21 a-(pl y p y -(P y y p 7 4-l3-[2-(Methylmercapto)- 4-l3-[2-(Methylmercapto)- benzyl chloride. benzyl.

phenothiazin-10-yl1propyll phen0thiazin-10yl]-propyll 22 (D- 9l y (D- D Y piperazinoethanol. piperazinoethyl. m hyl oride. methyl.

, ropyllplperazinoethanol. ropyllplperazinoethyl. 4O 24 m flpyn y (P- Y y 9 4- 3-[2-(Trifluorornethoxy)- 4- 3-[2-(Trifluoromethoxy)- chloride.

phenothiazin-l0-yl]- phenothiazin-lO-yl} propyllpiperazinoethanol. ropyllpiperazinoethyl.

enot 'azin-l eno 'azin- -y ropyupjpgrazin oethanoL pmpynpipemmoethy1 This invention may be variously otherwise embodied 11 within the scope of the appended claims.

ammosulfonyl) phenothiap ammosultonyl) phenothia- 40 zin-l0-y11propyllpiperzin-l0-yl]propyl}plper- What IS claimed 15: azmoethanolazmoethyl' l. A compound selected from the group consisting of Example 12.4-{3- [2-(trifluoromethyl)phenothiazin-10- yl] propyl}-p1'perazinoethoxyethyl benzhydryl ether Following the procedure of Example 1 but substituting an equivalent amount of 4-{3-[2-(trifluoromethyl)phenothiazin 10 yl]propyl}-piperazinoethoxyethanol for the piperazinoethanol used in the example, 4-{3-[2-(trifluoromethyl)phenothiazin 10 yl]propyl} piperazinoethoxyethyl benzhydryl ether is formed.

Example 13.4 {3 [2-(trifluoromethyl)phenothiazin- JO yl]propyl} piperazinoethyl benzhydryl ether, dimaleate salt To 6.03 g. of the pale yellow oil obtained in Example 1 in 25 ml. of warm acetonitrile is added a solution of 3.32 g. of maleic acid in 25 ml. of warm acetonitrile, with vigorous mixing. The clear solution which forms is allowed to cool slowly. The crystalline solidwhich separates is filtered and recrystallized from isopropanol to 1 bases of the formula wherein r is a positive integer less than three, and X, R and R are each selected from the group consisting of hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkoxy, lower alkanoyl, lower alkylmercapto, trifluoromethylmercapto, trifiuoromethoxy, N,N-dimethylaminosulfonyl and lower alkylsulfonyl; and non-toxic acidaddition salts thereof.

2. 4-{3-[2-(trifluoromethyl)phenothiazin -10 yl]propyl}-piperazinoethyl benzhydryl ether. 7

3. 4-[3-(2 chlorophenothiazin 1O yl)propyl]piperazinoethyl benzhydryl ether.

4. 4-{3-[2-(trifiuoromethyl)phenothiazin l0 yl]propyl}-piperazinoethoxyethyl benzhydryl ether.

5. A non-toxic acid-addition salt of 4-{3-[2-trifluoromethyl) phenothiazin- 1 O-yl] propyl}-piperazinoethyl benzhydryl ether.

7 6. 4-{3-[2-(trifluoromethyl)phenothiazin 10 yl]propyl}-piperazinoethyl a(chlorophenyl)benzyl ether.

References Cited by the Examiner UNITED STATES PATENTS 2,928,767 3/60 Gulesich et a1. 260--243 2,953,568 1 9/60 Werner 260-268 3,054,791 9/62 Yale et a1 260-243 ,FOREIGN PATENTS 4/60 Great Britain. 4/60 Great Britain.

Examiners. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA 